MIT scientists have created a method to “paint” GLP-1 drugs onto antibodies inside the body, achieving longer-lasting effects with smaller doses.
Glucagon-like peptide-1 (GLP-1) receptor agonists are peptide-based drugs used to treat diabetes and support weight loss. However, limited availability and high costs have made it challenging for many patients to begin or maintain therapy. In response, researchers have developed a novel drug delivery system that attaches GLP-1 peptides directly to the antibodies they target.
In mouse studies, this approach resulted in sustained weight loss and longer-lasting blood sugar control—using only one-fourth the standard GLP-1 dose.
Bradley Pentelute, a chemistry professor at the Massachusetts Institute of Technology (MIT), presented findings at the American Chemical Society (ACS) Spring 2025 meeting, which took place March 23–27. The conference featured approximately 12,000 presentations across a wide range of scientific topics.
Challenges of Peptide-Based Drugs
Peptide-based therapies are highly effective. However, they are easily degraded by enzymes in a person’s body because peptides lack the structural stability that larger, more complex proteins have. One way that scientists have tried to work around this limitation for GLP-1 receptor agonists is fusing the peptide directly to a person’s immunoglobulin G (IgG) antibodies. These long-acting, drug-fused IgGs act as excellent peptide ferries, but they are costly because the antibodies must be extracted and modified in a laboratory before they can be effective inside that same person’s body.
Pentelute and his team have developed a technology to attach GLP-1 receptor agonists to IgGs within the body. The drug delivery system, which he calls in vivo antibody painting, is itself a peptide and is composed of a binder region that attaches to the IgG, a payload region that carries the GLP-1 receptor agonist, and a reactive region that attaches (i.e., paints) the GLP-1 drug onto the IgG with a covalent bond.
In laboratory tests of the antibody painting platform on mouse and human IgGs, the researchers found that nearly half of all antibodies successfully attached to GLP-1 receptor agonists at a body temperature of 98.6 degrees Fahrenheit (37 degrees Celsius).
Promising Results in Mouse Models
Next, they tested the platform for delivering GLP-1 receptor agonists in a mouse model for Type 2 diabetes and metabolic-induced obesity. Pentelute and his colleagues found that the mice experienced sustained blood glucose management and weight loss for up to 15 days after a single treatment. In fact, mice that received antibody painting had better and longer lasting results at a GLP-1 drug dose much lower than the current traditionally administered dose.
The researchers have shared their findings in a preprint research article that is currently under peer review. Pentelute will expand upon this work during his ACS Spring 2025 presentation, including new results from demonstrations showing that the platform can effectively paint antibodies in the presence of extracellular debris such as cellular proteins.
“We’re also expanding the technology to make antibody drug conjugates for cancer,” shares Pentelute. “And we’re modifying this technology to be able to paint multiple drugs onto one antibody,” he adds. “With new technology like this, the future of peptide-based therapies could see reduced costs and enhanced effectiveness.”
Meeting: ACS Spring 2025
The research was funded by Pentelute’s discretionary funds at MIT and the National Cancer Institute at the National Institutes of Health.
This technology is included in a pending provisional patent from MIT. Katsushi Kitahara, a study co-author, is employed by a pharmaceutical company. Pentelute is a co-founder and involved with several companies focusing on the development of protein and peptide therapeutics.
